Respiratory stimulant comprising neon



United States Patent 3,436,455 RESPIRATORY STIMULANT COMPRISING NEONRichard A. Flinn, Emmaus, and Jack A. Young, Allentown, Pa., assignorsto Air Products and Chemicals Inc., Philadelphia, Pa., a corporation ofDelaware No Drawing. Filed Mar. 5, 1963, Ser. No. 263,065 Int. Cl. A6lk13/00 US. Cl. 424127 4 Claims This invention relates to respiratory gasmixtures and to compositions and methods for using such compositions toachieve advantageous physiological effects. For example, suchcompositions make it possible to increase the tidal flow of respiratorygas.

The noble gases include helium, neon, argon, krypton, xenon, and radon.Xenon has an anesthetic affect of significant magnitude. Helium is apreferred gas for utilization in respiratory gases at super atmosphericpressures,

as explained in Cooke 1,473,337 and Yant et al. 1,644,-

363. As explained in Cooke vs. United States, 80 United States PatentQuarterly 374, helium can diffuse from the body fluids with greaterrapidity than nitrogen, and thus can decrease the tendency toward thedevelopment of a dangerous illness sometimes called the bends. Therelative diffusion rates of gases are generally proportional to thesquare roots of their molecular weights, so that helium has a diffusionrate which is somewhat greater than twice that of nitrogen, whereas thepredicted diffusion rate of neon, based upon the ratio of square roots,is only about 16% greater than that of nitrogen. Thus, the incrementaldiffusion advantage for helium was known to be more than six timesgreater than any incremental diffusion advantage for neon. Accordingly,little interest has been shown in the untested possibility that neonmight diffuse from biological fluids more rapidly than nitrogen. Each ofthe Yant et a1. and Cooke patents clearly indicates that no testssubstituting neon for the preferred helium were conducted.

In accordance with the present invention, a respiratory gas compositionis characterized by the presence of a significant amount of neon. Therespiratory gas mixture must contain at least 2% by volume of neon, butnot more than about 80% by volume neon. The respiratory gas mixture mustcontain a concentration of oxygen suitable for sustaining life under thecircumstances employed, which life sustenance is conveniently designatedas fulfilling the respiration requirements of lungs, thus embracinganimal life having lungs but excluding vegetation, fish, and other lifenot having lungs supplying oxygen to circulating blood. The respiratorygas composition must contain sufficient oxygen for supplying oxygen tothe blood in the lungs or it would not be designated as a respiratorygas. At atmospheric pressure, a respiratory gas generally con tains 99%oxygen, but smaller amounts may suffice at high pressures. Therespiratory gas composition may or may not include other respiratorygases such as helium, nitrogen, cyclopropane, tetrafiuorornethane',carbon dioxide, and/or other gases having a desired function in arespiratory gas mixture of controlled composition. The concentration ofthe total of all other respiratory gases should desirably be not morethan nine times the volume of the mixture of oxygen and neon, and isgenerally less than four times the volume of the mixture of oxygen andneon.

The advantages of neon as a component of a respiratory gas mixture aresurprising, and different from what might have been predicted on thebasis of the known physiological effect of other gases. Among the usefulresults obtained by the advantageous respiratory gas compositions of thepresent invention are the increased minute volume of respiratory gas.Such use of neon increases the gas inhaled and exhaled by the lungsmeasured by the volume per minute. The use of neon may either increaseor decrease the breathing rate. Similarly, the use of neon may eitherincrease or decrease the volume per breath or tidal volume. The neoninhalant compositions achieving some of the most advantageous increasesof the minute volume also tend to decrease the breathing rate ascompared with the breathing rate employing air as the respiratory gasand to increase the tidal volume. The respiratory gas mixturecharacterized by a significant concentration of neon and containing aneffective amount of oxygen has other advantageous characteristics, butthe respiratory stimulant advantage is a convenient attribute forillustrating the superiority of such compositions.

The nature of the present invention is further clarified by a pluralityof examples.

Example I Five mongrel dogs were used in a series of five experiments.In preparing each dog for a test, the trachea was exposed and intubatedwith a cuffed endotracheal tube of maximum cross-sectional diameter. Theanimal was allowed to breath room air until accustomed to the presenceof the endotracheal tube. Tidal and minute volumes were measured with aWright Respirometer. The animal was connected to a HeidbrinkKinet-o-meter anesthesia machine after three successive and agreeingmeasurements of tidal volume had been obtained. A semi-closed circuitfor carbon dioxide adsorption was used. A sufficient flow of gas wasmaintained so that the reservoir bag was threequarters full and yet noflow was going through the respirometer except during activeinhalations. The pop-off valve was kept open to assure a lack ofpressure in the system.

Each dog was kept awake but was kept in a quiet state by controlledsupplemental injections of an aqueous solution (also containing 5%glucose) of sodium S-ethyl-S- (l-methylbutyl)-2-thiobarbiturate(Pentothal) using an Abbott microdrip attached to an intravenous needle.

In the various tests, the dogs breathed respiratory gas mixtures havingcode designations and compositions as follows: (1) 5% neon, 20% oxygen,and nitrogen; and (2) 10% neon, 20% oxygen, and 70% nitrogen. Thesegases were pre-blended and kept in metal cylinders under pressure.Connection from the cylinders to the gas machines was through aconventional regulator and high pressure hose, and flow was regulatedthrough a nitrous oxide flowmeter. The actual flow rate was of noconsequence since the flow was regulated through the requirements of thegas system as stated above.

An outlet was tied into the inhalation side of the circuit and a hoseled from the adapter to a Beckman Model D paramagnetic oxygen analyzer.Determination of the oxygen level was semi-continuously (about everyminute) and basal oxygen was added as required to maintain the gases ata 20% oxygen concentration. Heart sounds were monitored by a precardialstethoscope.

The data obtained from five experiments are given in Table I. From areview of the percentage changes it is seen that there were definiteincreases in tidal volume in each test in which a dog breathed a gascontaining 540% neon. The increases in volume of gas breathed per minutewere generally accompanied by decreases in the number of breaths perminute, or respiration rate. It is apparent that there is some variationin results from animal to animal.

Certain other observations were noted. The animals take the inhalationof neon Without fighting. Salivation is not excessive. There is noapparent pulmonary irritation. The increase in inhalation appears afterabout two minutes exposure and persists as long as neon is present inthe system. Neon exhibits no anesthetic properties whatsoever. Recoveryfrom neon is swift and complete in two to three minutes. Repeatedexposure does not result in tolerance. There were no cardiac changeswhich could be attributed to neon inhalation. Cardiac rate remainedrelatively constant and no arrhythmia was noted.

Although an attempt was made to keep sedation at a minimum, and althoughthe animals appeared to have a rather constant degree of consciousness,there is a significant possibility that a portion of the varyingrespiratory response to neon inhalation is attributable to a change inthe level of Pentothal sedation. The available evidence required theconclusion that the effect is apparently a unique heterostych of neon.Other members of the noble gas family do not function as respiratorystimulants. No good explanation is apparent for the wide variation inthe degree of change when different dogs are tested using the sameconcentration of neon. It was noted that repeated exposure of the sameanimal to the same concentration of neon results in similar responses.Thus, the

TABLE I Minute Respiration Tidal Change in Experimen- Neon volume rateavervolume tidal vl tal N 0. average age (numaverage ume (per- (liters)her/min.) (ca/breath) cent) variations in response must be attributed toundefined variations in individual animals. It was also noted that thefrequency of the respiratory rate usually decreased when increases intidal and minute volumes occurred. The nor mal respiratory change withmoderate neon concentrations is thus due to marked increases in tidalvolume.

A substantial stimulation of respiration does appear to result from thebreathing of neon-containing air mixtures. The stimulation results insignificantly increased tidal and minute volumes, along with a decreasein respiratory frequency. The magnitude of the effect varies with theconcentration of neon in the mixture and also varies from subject tosubject. Response to and recovery from the effect are quite rapid,occurring within several minutes.

EXAMPLE 2 Four dogs are anesthetized by injection with sodium 5 ethyl 5(l methylbutyl) 2 thiobarbiturate (Pentothal) to achieve a steady stateof breathing under the control conditions. Instruments are provided tomeasure: the volume of respiratory gas inhaled and exhaled per minute;the breathing rate; the volume of gas inhaled per breath, convenientlydesignated as tidal flow or tidal volume; and the rate of oxygenreplacement necessary for maintaining the oxygen concentrationsubstantially steady at about 20%. When the respiratory gas contains 1%neon, the increase in the volume of gas inhaled and exhaled per minuteis small enough that the stimulant effect is not clearly established. Byincreasing the neon concentration to about 2.0% by volume, the tidalfiow is measurably increased within ten minutes. When the dogs breathe amixture of 5% neon, 20% oxygen, and 75% nitrogen, the tidal flowincrease is measurable after about one minute. Mixtures providing about39% neon,

% oxygen, and 41% nitrogen are effective in increasing the tidal flow toapproximately more than observed when using air as the respiratory gas.Mixtures containing about 80% neon are less reliable by reason of themore extreme differences among different dogs when using such excessiveneon concentrations but the respiratory stimulant effect is advantageouseven at this expensively high concentration. The mixtures containing 80%neon and 20% oxygen produce results which accentuate the differences inthe response of individual dogs to neon inhalation. Mixtures consistingof 35% neon and oxygen increase both the tidal flow and the volume perminute, this mixture appearing to have potential usefulness whereverstimulating respiratory gases are employed. By a series of tests, it isestablished that the volume concentration of neon in the respiratory gasshould e within the range from 2% to about The oxygen concentration ofthe neon inhalant should be within the range suitable, under thecircumstances, for maintenance of life of species in which bloodcirculates for gas exchange in lungs, which concentration isconveniently designated as meeting the respiration requirements oflungs. The oxygen concentration at at mospheric pressure is generallywithin the range from 21% to 98% by volume, but at superatmosphericpressure, smaller concentrations of oxygen are sufficient to meet therespiration requirements of the lungs. The mixture of neon and oxygenmust constitute at least 10% by volume of the inhalant composition.Other respiratory gases such as nitrogen, helium, cyclopropane,tetrafluoromethane, and/or other gases employed as anesthetics, as inertdiluents, and/or as medicants having a controlled physiological actionmust be not more than nine times the volume of the neon-oxygen mixture,that is, the concentration of such other respiratory gases, if present,must be not more than or if expressed by two limits, within the rangefrom 0 to 90%.

Example 3 Control measurements establish for each of eight dogsbreathing air the volume per minute, the volume per breath (i.e. tidalvolume) and the breaths per minute (i.e. breathing rate). Each dog istested using an inhalant composition consisting of 20% oxygen, 40%helium, and 40% neon. Notwithstanding differences in the magnitude ofthe response, the volume breathed per minute increased significantly foreach dog.

When a respiratory stimulant is helpful, the principal goal is theresult of larger minute volume, so that the blood may be exchanged witha larger volume of gas per minute. Such increase is desirablyaccompanied by deeper breathing (increased volume per breath or largertidal volume) inasmuch as rapid shallow breathing (even when achievingincreased minute volume) stimulates excitement and other disadvantageouscharacteristics. In the usual situation, the increased tidal volume isso related to the increased minute volume that the number of breaths perminute is decreased. Thus, the desired effect is increased, deeper,slower breathing, but the increased breathing may involve either fasteror slower rates and either deeper or shallower breathing depending onthe overall effect on volume per minute.

Various modifications of the invention are possible without departingfrom the scope of the invention as set forth in the appended claims.

What is claimed is:

1. The method of stimulating mammals having lungs to inhale respiratorygas at a rate expressed in volumes per minute which is greater thannormal, which method is characterized by providing to the lungs arespiratory gas mixture consisting essentially of: from 2 to about 80%neon; from 21 to 98% oxygen; an inert respiratory gas an anestheticrespiratory gas, and a medicant respiratory gas, the total concentrationof. inert, anesthetic, and medicant respiratory gases being less thannine times the volume concentration of the sum of the volumeconcentration of the mixture of neon and oxygen.

2. The method of claim 1 in which the mammals are dogs.

3. A respiratory gas composition consisting essentially of: from 2 toabout 80% neon; from 21 to 98% oxygen, said neon acting to stimulate thelungs of mammals having lungs to inhale respiratory gas at a rateexpressed in volumes per minute which is greater than the rate at whichair is normally inhaled.

4. The method of stimulating lungs in mammals to inhale an increasedvolume of respiratory gas which con sists of providing the lungs of saidmammals a respira- References Cited UNITED STATES PATENTS 1,473,33711/1923 Cooke 167-526 10 FRANK CACCIAPAGLIA, JR., Primary Examiner.

J. D. GOLDBERG, Assistant Examiner.

1. THE METHOD OF STIMULATING MAMMALS HAVING LUNGS TO INHALE RESPIRATORYGAS AT A RATE EXPRESSED IN VOLUMES PER MINUTE WHICH IS GREATER THANNORMAL, WHICH METHOD IS CHARACTERIZED BY PROVIDING TO THE LUNGS ARESPIRATORY GAS MIXTURE CONSISTING ESSENTIALLY OF: FROM 2 TO ABOUT 80%NEON; FROM 21 TO 98% OXYGEN; AN INERT RESPIRATORY GAS AN ANESTHETICRESPIRATORY GAS, AND A MEDICANT RESPIRATORY GAS, THE TOTAL CONCENTRATIONOF INERT, ANESTHETIC, AND MEDICANT RESPIRATORY GASES BEING LESS THANNINE TIMES THE VOLUME CONCENTRATION OF THE SUM OF THE VOLUMECONCENTRATION OF THE MIXTURE OF NEON AND OXYGEN.